There is converging preclinical and clinical evidence that GABAergic deficits are an important factor in major depressive disorders (MDD). However, the neuronal circuits in which these deficits exist and the individual GABAA receptor subtypes that modulate depressive-like behavior are unknown. By analyzing the response to chronic social defeat stress, a rodent model of depression with construct, face, and predictive validity, we propose to study how a2- and a3-containing GABAA receptors in defined neuronal circuits play a role in the behavioral transition from a normal state to a down (i.e. depressed) state and vice versa. Using a novel genetic-pharmacological approach we will further assess whether a highly a2- specific [or a3-specific] agonist administered during social defeat can prevent [or promote] the transition from the normal state to the down state. We will also assess whether such an agonist can acutely promote [or prevent] the transition from the depressed state back to the normal state when administered after cessation of chronic social defeat. The proposed studies are expected to demonstrate that a2-specific agonism generates an acute antidepressant-like effect and will provide proof-of-concept for the development of a novel class of antidepressant agents. PUBLIC HEALTH RELEVANCE: Currently available antidepressant drugs target monoaminergic or serotonergic systems, take several weeks to develop their therapeutic effects and do not work in all depressed patients; thus, there is an urgent need to develop antidepressants which have a rapid onset of action and/or which have targets distinct from those of the currently available drugs. We propose to examine the role of individual GABAA receptor subtypes in modulating transitions between normal and down/depressed states and expect that a2- and a3-containing GABAA receptors have opposing functions; specifically that a2-containing GABAA receptors will exert antidepressant-like actions whereas a3-containing GABAA receptors will have prodepressant-like effects, and that pharmacological agonism of a2-containing GABAA receptors will have an acute antidepressant-like action. By directing our research at previously unrecognized potential drug targets, we expect to provide proof-of-principle for the development of novel pharmacological agents with a more rapid onset of action.